Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.Cl.[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH-:17].[Na+]>S(=O)(=O)(O)O>[OH:17][C:8]12[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][C:6]([NH2:16])([CH2:15]3)[CH2:7]1)[CH2:14]2
Reactant: [OH-]
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: NC12CC3CC(C1)CC(O)(C3)C2
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a mixture of 150 ml of concentrated sulfuric acid and 15 ml of concentrated nitric acid, cooled to 10° C. is added 10 g (0.053 moles) of 1-adamantanamine hydrochloride over 5 minutes. This mixture is stirred in an ice bath for 4 hours. The reaction is then poured over ice and the pH adjusted to pH 10 using 50% NaOH. The product is extracted into chloroform which is dried over MgSO4 and then evaporated to dryness. The residue is recrystallized from ethyl acetate to give 3-hydroxytricyclo[3.3.1.13,7 ]decan- 1-amine (m.p. 260°-264° C.) which is used directly is step B.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1(C(O)=O)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC#N>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([NH2:39])([CH2:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=2[CH3:1])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
To a mixture of 4-(2-methylbenzyl) N-t-butoxycarbonyl isonipecotic acid (1.0 g, 3.0 mmol) in CH3CN (20 ml) add diphenyl phosphoryl azide (0.99 g, 3.6 mmol) and triethylamine (0.50 ml, 3.6 mmol). After stirring at 55° C. (oil bath temp.) concentrate the reaction in vacuo and partion the residue between EtOAc and saturated aqueous NaHCO3. The organic phase is washed with brine, dried (MgSO4), and concentrated in vacuo to afford the crude product.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:16][C:11]=2[S:10][C:9]1=[N:22]C(=O)C(F)(F)F)(=O)=O.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CO.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH:22]=[C:9]1[N:8]([CH2:7][CH2:6][N:39]2[CH2:40][CH2:41][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:29])[CH2:37][CH2:38]2)[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:16][C:11]=2[S:10]1
Reactant: CS(=O)(=O)OCCn1c(=NC(=O)C(F)(F)F)sc2cc(OC(F)(F)F)ccc21
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccccc1N1CCN(CCn2c(=N)sc3cc(OC(F)(F)F)ccc32)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
Using the procedure described in Example 1, starting with 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (5.88 g) in toluene (200 cc) and 4-(2-methylphenyl)piperazine (6.87 g) and after 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure. To the residue thereby obtained, methanol (100 cc) and a 7% strength aqueous-alcoholic solution (20 cc) of potassium carbonate are added and the mixture is stirred for 2 hours at approximately 20° C. The alcohol is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column with a dichloromethane/ethyl acetate mixture (70:30 by volume) as eluent, and then an ethyl acetate/cyclohexane mixture (50:50 by volume) as eluent. 2-Imino-3-{2-[4-(2-methylphenyl)-1-piperazinyl]ethyl}-6-trifluoromethoxybenzothiazoline (1.8 g), m.p. 135° C., is thereby obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[N:4]1)[CH3:2].[NH:17]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:18]2[N:17]=[CH:23][C:6]3[CH:5]=[N:4][N:3]([C:1]4[N:24]=[C:20]([N:17]5[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19][CH2:18]5)[CH:21]=[CH:22][CH:2]=4)[C:7]=3[CH:19]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCCNCC1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCC(N)CC3)n2)cn1
Yield: 12 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl azepan-4-ylcarbamate, 140 was obtained as an off-white solid (16.2 mg, 12%) over 2 steps. 1H NMR (400 MHz, DMSO) δ 9.15-9.11 (s, 1H), 8.70-8.65 (d, J=9.8 Hz, 1H), 8.54-8.47 (d, J=8.1 Hz, 1H), 8.28-8.25 (d, J=7.4 Hz, 1H), 7.95-7.87 (s, 1H), 7.73-7.66 (dd, J=10.5, 5.7 Hz, 1H), 7.18-7.12 (d, J=7.7 Hz, 1H), 6.60-6.54 (t, J=6.6 Hz, 1H), 4.25-4.18 (q, J=7.3 Hz, 2H), 3.95-3.86 (s, 1H), 3.85-3.77 (m, 1H), 3.75-3.58 (ddd, J=20.2, 14.0, 9.4 Hz, 2H), 2.94-2.85 (dd, J=12.2, 6.3 Hz, 1H), 2.07-1.96 (m, 2H), 1.83-1.74 (m, 1H), 1.74-1.66 (d, J=14.4 Hz, 1H), 1.65-1.56 (ddd, J=13.0, 9.1, 4.5 Hz, 1H), 1.46-1.41 (t, J=7.3 Hz, 3H), 1.42-1.34 (dd, J=14.2, 4.0 Hz, 1H); MS (ESI) m/z: 403.2 [M+H]+
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)=O.[NH2:25][NH2:26]>>[CH3:21][S:18]([C:14]1[CH:13]=[C:12]([C:9]2[S:8][C:7]([C:5]3[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[NH:26][N:25]=3)=[CH:11][CH:10]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:19].[NH:25]1[CH:4]=[CH:3][CH:2]=[N:26]1
Reactant: NN
Reactant: CS(=O)(=O)c1cccc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)c1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)[nH]n3)s2)c1
Product: c1cn[nH]c1

Procedure:
Another method used for preparing examples of the invention is shown as Example 60. 4,4,4-Trifluoro-1-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-butane-1,3-dione was condensed directly with hydrazine to form pyrazole 3-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-5-trifluoromethyl-1H-pyrazole. Alkylation of a pyrazole such as 3-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-5-trifluoromethyl-1H-pyrazole could result in a mixture of positional isomers which could be separated by one skilled in the art
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]=O)=[O:16])=[CH:11][C:10]=1[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(CCN)=CC=1)(OC)=O.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[NH2:46])=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:46][CH2:17][CH:15]([OH:16])[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH2:19][OH:20])[CH:11]=2)([CH3:47])[CH3:48])=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35]
Reactant: O=CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: COC(=O)c1ccc(CC(C)(C)N)cc1
Agent: COC(=O)c1ccc(CCN)cc1
Product: COC(=O)c1ccc(CC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c(CO)c2)cc1

Procedure:
The title compound was prepared by the process of Example 25, replacing phenyl glyoxal by 4-benzyloxy-3-hydroxymethylphenyl glyoxal and 2-(4-carbomethoxyphenyl)ethanamine by 2-(4-carbomethoxyphenyl)-1,1-dimethylethanamine. τ (d6DMSO) 9.06 (6H, s), 7.10-7.60 (5H, m), 6.20 (3H, s), 5.39 (2H, s), 5.00 (1H, m), 4.88 (2H, s), 3.04 (2H, d, J=8 Hz), 2.40-3.00 (10H, m), 2.12 (2H, d, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12]O)=[C:4]([CH2:14]O)[CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.C(N(CC)C(C)C)(C)C.[C:37]1([C:43]([NH2:56])([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9])[CH2:12][N:56]([C:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:14]2
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(F)c(C(F)(F)F)cc1CO
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: Fc1cc2c(cc1C(F)(F)F)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.56 mmol (4-fluoro-2-hydroxymethyl-5-trifluoromethyl-phenyl)-methanol and 0.08 mmol DMAP in 5 ml dichloromethane at 0° C. were added dropwise 3.28 mmol methanesulfonyl chloride and 6.25 mmol triethylamine. The mixture was stirred at 0° C. for 1 h, and then heated quenched with water. The mixture was extracted with dichloromethane and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in DMF and then 4.68 mmol N,N-diisopropylethylamine and 2.03 mmol triphenylmethylamine were added sequentially. The mixture was heated at 60° C. for 1 day and then at 80° C. for a further day. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a white amorphous solid (23% yield). EI-MS (m/e): 370.1 ([M−Ph]+, 100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH:24]([CH3:26])C)[NH:13][C:12](=[O:27])[CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:29][NH2:30]>C(O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH2:24][CH3:26])[NH:13][C:12](=[O:27])[CH:11]=3)[CH:6]=2)[NH:30][N:29]=1
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc(F)c(C#N)c2)cc(=O)[nH]1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)cc(=O)[nH]1
Temperature: 100 °C

Procedure:
A mixture of 2-fluoro-5-(6-{2-[(2-methylpropyl)oxy]phenyl}-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile (50 mg), and hydrazine hydrate (2 mL) in ethanol (10 mL)was heated to 100° C. for 3 h. The reaction mixture was concentrated and the product was purified by preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate) to afford 4-(3-amino-1H-indazol-5-yl)-6-[2-(propyloxy)phenyl]pyridin-2(1H)-one (20 mg). 1H NMR (400 MHz, d4-CD3OD): δ 8.18 (s, 1H), 7.72 (d, 1H), 7.57 (d, 1H), 7.46 (t, 1H), 7.39 (d, 1H), 7.16-7.08 (m, 2H), 6.92 (d, 1H), 6.76 (s, 1H), 3.88 (d, 2H), 2.12-2.05 (m, 1H), 1.00 (d, 6H). MS (EI) for C22H22N4O2: 375 (MH±).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH2:10][CH2:9]2.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:9]2
Reactant: O=Cc1cccs1
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1ccc2c(c1)CCN(Cc1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of sodium cyanoborohydride is added to a solution of 1.5 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline, 1.2 g of thiophene-2-aldehyde and 1.8 g of toluenesulfonic acid monohydrate in 30 ml of ethanol. The mixture is stirred at room temperature for 8 hours, the solvent is removed in vacuo, and the residue is taken up with water/methylene chloride. The organic phase is again skaken with water, dried and evaporated in a rotary evaporator. The crude oily product is purified by chromatography on silica gel using a mixture of ethyl acetate/methylene chloride in the ratio 1:2. 1.7 g of a colorless oil, which crystallizes on standing (69% of theory), is obtained. Melting point: 110°-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)CBr
Reactant: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(Br)cc1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
A mixture of 4-bromo-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (710 mg, 1.87 mmol), 1-bromo-2-methyl propane (305 μL, 2.80 mmol) and K2CO3 (412 mg, 2.99 mmol) in DMF (5 mL) was heated at 90° C. for 18 hours. The cooled mixture was diluted with EtOAc, washed with water (3×) and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-15% EtOAc in cyclohexane) and triturating with pentane gave 4-bromo-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (562 mg, 69% yield) as a colourless crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.72-7.55 (m, 2H), 7.57-7.56 (m, 2H), 7.58-7.43 (m, 2H), 7.13-7.09 (m, 1H), 3.53-3.08 (m, 2H), 1.66-1.63 (m, 1H), 0.90 (d, J=6.5 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H), LCMS (m/z, Method A) ES+ 436.0 [M+1]+.
Reaction SMILES: [C:1](#[N:4])[CH2:2]O.[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][NH2:10])[CH3:6]>>[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][NH:10][CH2:2][C:1]#[N:4])[CH3:6]
Reactant: CCOC(CN)OCC
Reactant: N#CCO
Product: CCOC(CNCC#N)OCC

Procedure:
A mixture of glycolonitrile (8.33 g, 70% solution in water, 0.1 mol) and aminoacetaldehyde diethyl acetal (14.5 mL, 0.1 mol) was heated to reflux for 3 h. After cooling, the mixture was filtered to remove traces of solid and the filtrate then concentrated in vacuo to give the desired product 4.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C([OH:25])C.OO.O>[OH-].[Na+]>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]2[NH:2][C:1](=[O:25])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][C:4]=3[N:9]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1cccnc1NC(=O)CCCCCc1ccccc1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(CCCCCc2ccccc2)nc2ncccc12

Procedure:
To 6-phenyl-hexanoic acid (3-cyano-pyridin-2-yl)-amide (360 mg, 1.2 mmol) in sodium hydroxide (6 ml, 5M) was added ethanol (0.1 ml) and hydrogen peroxide (3% in H2O, 1.5 ml). The reaction mixture was heated to reflux for 3 hours. Water was added, the solution was acidified (pH 5) and extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over Na2SO4, filtrated and concentrated in vacuo. Column chromatography on silica gel with CH2Cl2:MeOH 9:1 as eluent, followed by trituration from diethyl ether yielded 2-(5-phenyl-pentyl)-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid, MS (m/e): 294.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[ClH:1].[CH2:30]([O:24][C:23]([C:18]1([C:20]([O:22][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCc1ccccc1
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCc1ccccc1)(C(=O)OCc1ccccc1)O2)NCC(O)c1cccc(Cl)c1
Product: Cl

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and benzyl alcohol according to the procedure of Example I as a gummy white solid: 1H NMR (300 MHz, CDCl3): δ 1.26-1.32 (m, 3H), 2.76 (brt, 1H), 3.01-3.21 (brm, 2H), 3.36-3.49 (brm, 2H), 5.24 (s, 4H), 5.41 (d, J=9.5 Hz, 1H), 6.70-6.88 (m, 3H), 7.12-7.44 (complex m, 14H), 8.70-8.83 (brs, 1H), 9.95-10.10 (brs, 1H); MS (ES) m/z (relative intensity): 602 (M+, 100).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[C:13]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:14]([C:19]([N:21]2[CH2:24][C:23]([CH2:26][CH2:27][OH:28])([OH:25])[CH2:22]2)=[O:20])[CH:15]=[CH:16][C:17]=1[F:18].C(N(CC)CC)C>ClCCl>[F:11][C:12]1[C:13]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:14]([C:19]([N:21]2[CH2:24][C:23]([CH2:26][CH:27]=[O:28])([OH:25])[CH2:22]2)=[O:20])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(CCO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
A solution of oxalyl chloride (13 μL, 0.15 mmol) in dichloromethane (1 mL) was cooled to −78° C., and DMSO (22 μL, 0.31 mmol) was then added. To this mixture was added 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxyethyl)azetidin-3-ol (67.8 mg, 0.14 mmol) as a suspension in dichloromethane (1 mL). After stirring at −78° C. for 10 min, triethylamine (78 μL, 0.56 mmol) was added and the mixture was allowed to warm to rt. The solution was diluted with dichloromethane, and washed with 0.5 N HCl. The aqueous phase wash then extracted with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to provide [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]acetaldehyde as a white solid (22.1 mg, 0.045 mmol, 32% yield). 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 8.46 (s, 1H), 7.39 (m, 1H), 7.33 (m, 1H), 7.11 (m, 1H), 6.81 (m, 1H), 6.61 (m, 1H), 4.32-3.96 (br m, 4H), 3.41 (t, 2H), 3.07 (s, 1H); MS (EI) for C18H14F3IN2O3: 491 (MH+).
Reaction SMILES: C[CH:2]1[CH2:5][CH2:4][C:3]1=[O:6].[CH2:7]([Mg]Br)[CH:8]=[CH2:9].O.[CH2:13]1COCC1>>[CH2:7]([C:3]1([OH:6])[CH2:2][CH:5]([CH3:13])[CH2:4]1)[CH:8]=[CH2:9]
Reactant: C1CCOC1
Reactant: CC1CCC1=O
Reactant: C=CC[Mg]Br
Solvent: O
Product: C=CCC1(O)CC(C)C1
Yield: 46.9 %

Procedure:
Methylcyclobutanone (3.200 g, 38.043 mmol) was dissolved in 200 ml THF and allylmagnesium bromide (190.21 ml, 190.21 mmol) was added in one portion. The mixture was stirred for 4 h at RT, hydrolyzed with water and extracted. The combined organic extracts were dried over MgSO4 and evaporated and purified via glass col. Chrom. (25-75% hex. in EtOAc). 1-Allyl-3-methylcyclobutanol (2.250 g, 46.9% yield) was obtained as a mixture of cis-trans isomers approx 4:1 (where the major compound is the one Me-cis to OH) based on NMR.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:49])=[CH:21][CH:20]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(-c3ccccc3)nc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(-c3ccccc3)nc21
Yield: 72.1 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-{4-(3-methyl-5-phenyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 111) was treated with 36 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 420 mg of the title compound, melting at 211-213° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:14]([CH2:15][P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[O:13][C@@H:12]([C:22]([F:25])([F:24])[F:23])[C@H:11]2[O:26]C(C)(C)[O:28][C@@H:10]12)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.O>CCOC(C)=O>[OH:8][C@H:9]1[C@H:10]([OH:28])[C@H:11]([OH:26])[C@H:12]([C:22]([F:24])([F:23])[F:25])[O:13][C@H:14]1[CH2:15][P:16](=[O:21])([O:17][CH3:18])[O:19][CH3:20]
Reactant: COP(=O)(C[C@@H]1O[C@@H](C(F)(F)F)[C@H]2OC(C)(C)O[C@H]2[C@@H]1O[Si](C)(C)C(C)(C)C)OC
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COP(=O)(C[C@@H]1O[C@@H](C(F)(F)F)[C@@H](O)[C@@H](O)[C@@H]1O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 mL round bottom flask, dimethyl (((3aS,4R,6R,7S,7aR)-7-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-4-(trifluoromethyl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methyl)phosphonate (70 mg, 0.14 mmol) was taken up in a TFA-H2O mixture (2 mL, 9:1) at 0° C. The reaction mixture was gradually warmed to rt and stirred at rt for 3 h. Upon completion of the reaction (TLC, 50% EtOAc in hexanes, Rf 0.1), the reaction mixture was concentrated under reduced pressure. The residue obtained was washed with n-pentane (10 mL) to give dimethyl (((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(trifluoro methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate that was used in next step without purification (40 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 4.54-4.50 (m, 1H), 4.25-4.19 (m, 1H), 4.08-3.97 (m, 2H), 3.77 (d, J=6.0 Hz, 3H), 3.73 (d, J=6.0 Hz, 3H), 3.58-3.54 (m, 1H), 1.58 (s, 3H), 2.44-2.16 (m, 2H); 19F NMR (376.17 MHz, CDCl3) δ −74.36 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:3]=[CH:4][C:5]=1[F:26])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1
Reactant: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Reactant: OB(O)c1cccnc1
Product: Cc1cc(C2(c3cc(-c4cccnc4)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 37 %

Procedure:
The title compound was synthesized as described for Example 1 in 37% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.19 mmol) and pyridin-3-ylboronic acid (30.9 mg, 0.25 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].O[CH:13]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C1(C)C=CC=CC=1>[CH3:11][C:6]1[C:7](=[O:10])[C:8]([CH3:9])=[C:2]([CH3:1])[C:3](=[O:4])[C:5]=1[CH:13]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: COc1ccc(C(O)CCCCC(=O)O)cc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCCCC(=O)O)C2=C(C)C(=O)C(C)=C(C)C2=O)cc1
Temperature: 70 °C
Yield: 68.8 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (60 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mole) and 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (5.0 g, 0.021 mole), and the mixture was heated at 70° C. for 20 hours, with stirring. The reaction solution was evaporated under reduced pressure, and tetrahydrofuran (50 ml) was added to dissolve the residue, followed by adding furthermore a 10% aqueous solution of ferric chloride and stirring at room temperature for 10 minutes. The reaction product was extracted with ethyl acetate, and the organic layer was washed with water, dried and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether to give 6-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-6-(4-methoxyphenyl)hexanoic acid (5.1 g, 76%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 23 to 34 and 68 were prepared.